Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans

The sterol regulatory element binding proteins (SREBPs) are transcription factors that govern cholesterol and fatty acid metabolism. We recently identified SPRING as a post-transcriptional regulator of SREBP activation. Constitutive or inducible global ablation of Spring in mice is not tolerated, an...

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Vydáno v:	Nature communications Ročník 14; číslo 1; s. 5181 - 15
Hlavní autoři:	Hendrix, Sebastian, Kingma, Jenina, Ottenhoff, Roelof, Valiloo, Masoud, Svecla, Monika, Zijlstra, Lobke F., Sachdev, Vinay, Kovac, Kristina, Levels, Johannes H. M., Jongejan, Aldo, de Boer, Jan F., Kuipers, Folkert, Rimbert, Antoine, Norata, Giuseppe D., Loregger, Anke, Zelcer, Noam
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 25.08.2023 Nature Publishing Group Nature Portfolio
Témata:	13/1 13/106 14/63 38/39 38/43 38/77 38/90 38/91 45/41 631/208/457/649 631/443/319/1642 631/45/287/1183 631/45/287/1191 631/45/287/1197 64/60 82/58 82/80 96 Ablation Animals Biosynthesis Cholesterol Diet Fatty acids Female Genetic diversity Hepatocytes High density High density lipoprotein Humanities and Social Sciences Humans Life Sciences Lipid Metabolism Lipids Lipoproteins Lipoproteins, HDL Liver Male Metabolism Mice multidisciplinary Post-transcription Proteomics Regulatory sequences Science Science (multidisciplinary) Steatosis Sterol Regulatory Element Binding Protein 1 Sterol regulatory element-binding protein Transcription factors Transcriptomics Triglycerides
ISSN:	2041-1723, 2041-1723
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Shrnutí:	The sterol regulatory element binding proteins (SREBPs) are transcription factors that govern cholesterol and fatty acid metabolism. We recently identified SPRING as a post-transcriptional regulator of SREBP activation. Constitutive or inducible global ablation of Spring in mice is not tolerated, and we therefore develop liver-specific Spring knockout mice (LKO). Transcriptomics and proteomics analysis reveal attenuated SREBP signaling in livers and hepatocytes of LKO mice. Total plasma cholesterol is reduced in male and female LKO mice in both the low-density lipoprotein and high-density lipoprotein fractions, while triglycerides are unaffected. Loss of Spring decreases hepatic cholesterol and triglyceride content due to diminished biosynthesis, which coincides with reduced very-low-density lipoprotein secretion. Accordingly, LKO mice are protected from fructose diet-induced hepatosteatosis. In humans, we find common genetic SPRING variants that associate with circulating high-density lipoprotein cholesterol and ApoA1 levels. This study positions SPRING as a core component of hepatic SREBP signaling and systemic lipid metabolism in mice and humans. Hendrix et al show that absence of hepatic Spring dramatically lowers levels of lipids in the liver and plasma in mice, and protects from development of diet-induced steatosis. In line, genetic variation in SPRING is associated with lipid levels in humans.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 PMCID: PMC10457316
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-023-40943-1